Halogenated aniline and method for producing same

ABSTRACT

The present invention provides a halogenated aniline represented by formula (I) (wherein each of X 1  and X 2  independently represents a chlorine atom, a bromine atom or an iodine atom), a method for producing the halogenated aniline, and other aspects.

This application is a Divisional of U.S. application Ser. No.14/652,913, which is the U.S. National Stage application ofPCT/JP2013/084300, filed Dec. 20, 2013, which claims priority fromJapanese Patent Application No. 2012-280691, filed Dec. 25, 2012, thecontent of which is incorporated herein by reference.

TECHNICAL FIELD

The present invention relates to a novel halogenated aniline, which canbe used as a production raw material for compounds that are useful aselectronic materials, medicines, and agricultural chemicals and thelike, as well as a method for producing the halogenated aniline.

BACKGROUND ART

The compound 2,3-difluoroaniline is the starting raw material forproducing2-[2-fluoro-6-(7,8-difluoro-2-methylquinolin-3-yloxy)phenyl]propan-2-oland 2-[2-fluoro-6-(7,8-difluoroquinolin-3-yloxy)phenyl]propan-2-ol,which are known as active ingredients for agricultural and horticulturalgermicides (Patent Document 1).

Further, 2,3-difluoroaniline is also used in the production of medicinessuch as antibiotics (Patent Document 2), c-Met protein kinase inhibitors(Patent Document 3), drugs for Alzheimer's disease (Patent Document 4),Aurora B kinase inhibitors (Patent Document 5), and drugs forneuropathic pain (Patent Document 6).

Moreover, 2,3-difluoroaniline is also used in the production ofelectronic materials such as the azo compounds contained in compositionsfor anisotropic films that exhibit high dichroism, which are useful inthe polarizing plates and the like fitted to display elements such asliquid crystal display elements (LCD) and organic electroluminescentdisplay elements (OLED) (Patent Document 7).

In this manner, 2,3-difluoroaniline is useful as a production rawmaterial for electronic materials, medicines and agricultural chemicals,and a simple method for producing 2,3-difluoroaniline cheaply and inlarge quantities has been keenly sought.

One example of a known method for producing 2,3-difluoroaniline involvesfluorinating 2,3-dichloronitrobenzene to obtain3-chloro-2-ftluoronitrobenzene, hydrogenating the3-chloro-2-fluoronitrobenzene to obtain 3-chloro-2-fluoroaniline, usingthe Schiemann reaction to convert the 3-chloro-2-fluoroaniline to2,3-difluorochlorobenzene, and then performing an amination reactionwith a copper catalyst to produce 2,3-difluoroaniline (Patent Document8).

This method requires high temperature and high pressure in thefluorination reaction and the amination reaction, and uses chemicalreagents that are difficult to handle such as Raney nickel, and cantherefore not really be claimed to be an industrially useful method.

Patent Document 9 discloses that 2,3-difluoroaniline can be obtained byfluorinating 1,2,3-trichlorobenzene to obtain 2,3-difluorochlorobenzene,and then aminating the 2,3-difluorochlorobenzene using a coppercatalyst.

However, in this method, a regioisomer (2,6-difluorochlorobenzene) isproduced as a by-product during the fluorination, and therefore theyield of 2,3-difluorochlorobenzene is low. Further, the separation ofthe 2,3-difluorochlorobenzene from the by-product regioisomer isextremely difficult. Moreover, high temperature and high pressureconditions are required in the fluorination and amination reactions,meaning this method can also not be claimed to be industrially useful.

Patent Document 10 discloses a method for producing 2,3-difluoroanilineby hydrogenating 2,3-difluoronitrobenzene at high pressure.

This method is simple, having only one step, and is industriallyfeasible, but the raw material 2,3-difluoronitrobenzene is extremelydifficult to obtain, and the only known method in the literatureinvolves oxidation of the target material 2,3-difluoroaniline.

Patent Document 11 discloses a method for producing 2,3-difluoroanilineby hydrogenating 2,3-difluoro-4-chloro-nitrobenzene. However, in thismethod also, the raw material 2,3-difluoro-4-chloro-nitrobenzene isextremely difficult to obtain.

As described above, currently known methods for producing2,3-difluoroaniline require high temperature and high pressurereactions, and not only are the equipment costs high due to therequirement for special production equipment, but safety and stabilityoperations are also a significant burden.

PRIOR ART LITERATURE Patent Documents

Patent Document 1: WO2011/081174

Patent Document 2: WO2010/091272

Patent Document 3: WO2009/045992

Patent Document 4: WO2009/106750

Patent Document 5: WO2006/129064

Patent Document 6: WO2009/029592

Patent Document 7: JP 2010-026024 A

Patent Document 8: CN 101245020

Patent Document 9: U.S. Pat. No. 5,091,580

Patent Document 10: CN 101811973

Patent Document 11: JP 07-309815 A

DISCLOSURE OF INVENTION Problems to be Solved by the Invention

An object of the present invention is to provide a novel halogenatedaniline that can be used to produce 2,3-difluoroaniline and the like viaa simple process that avoids the requirement for high temperature andhigh pressure conditions, 2,3-difluoroaniline being a production rawmaterial for2-[2-fluoro-6-(7,8-difluoro-2-methylquinolin-3-yloxy)phenyl]propan-2-oland 2-[2-fluoro-6-(7,8-difluoroquinolin-3-yloxy)phenyl]propan-2-ol andthe like, which are useful as agricultural and horticultural germicidesthat can be used safely and with reliable effect. Another object of theinvention is to provide a simple method for producing the halogenatedaniline cheaply and in large quantities.

Means for Solving the Problems

The inventors of the present invention conducted intensiveinvestigations aimed at achieving the above objects. As a result, theydiscovered a novel halogenated aniline that could be used to produce2,3-difluoroaniline via a simple process that avoided the requirementfor high temperature and high pressure conditions. Further, they alsodiscovered a method for producing the novel halogenated aniline of thepresent invention which avoided high temperature and high pressureconditions and enabled the halogenated aniline to be produced cheaply,simply and in large quantities, by using 1,2-difluorobenzene as thestarting raw material, halogenating this 1,2-difluorobenzene, nitratingthe thus obtained 1,2-difluoro-4,5-dihalogenobenzene to produce ahalogenated nitrobenzene containing a novel halogenated nitrobenzene ofthe present invention, and then reducing the halogenated nitrobenzene toproduce the novel halogenated aniline of the present invention.Furthermore, they also discovered a method for producing2,3-difluoroaniline which avoided high temperature and high pressureconditions and enabled the 2,3-difluoroaniline to be produced cheaply,simply and in large quantities, by reducing and dehalogenating thehalogenated nitrobenzene containing the novel halogenated nitrobenzeneof the present invention. The present invention was completed byconducting further investigations based upon these findings.

In other words, the present invention includes the aspects describedbelow.

In formula (I), each of X¹ and X² independently represents a chlorineatom, a bromine atom or an iodine atom.

In formula (IIa), each of X^(1a) and X^(2a) independently represents achlorine atom, a bromine atom or an iodine atom, but the case in whichX^(1a) and X^(2a) both represent bromine atoms is excluded.

In formula (III), each of X¹ and X² independently represents a chlorineatom, a bromine atom or an iodine atom.

In formula (II), each of X¹ and X² independently represents a chlorineatom, a bromine atom or an iodine atom.

[1] A halogenated aniline represented by formula (I).

[2] A halogenated nitrobenzene represented by formula (IIa).

[3] A method for producing 2,3-difluoroaniline, including:

a step of halogenating 1,2-difluorobenzene or a1-halogeno-3,4-difluorobenzene to obtain a halogenated benzenerepresented by formula (III),

a step of nitrating the halogenated benzene to obtain a halogenatednitrobenzene represented by formula (II),

a step of reducing the halogenated nitrobenzene to obtain a halogenatedaniline represented by formula (I), and

a step of subsequently dehalogenating the halogenated nitrobenzene.

[4] The method for producing 2,3-difluoroaniline disclosed above in [3],wherein the 1,2-difluorobenzene or 1-halogeno-3,4-difluorobenzene ishalogenated using a Lewis acid catalyst.

[5] A method for producing a halogenated nitrobenzene, including:

a step of halogenating 1,2-difluorobenzene or a1-halogeno-3,4-difluorobenzene to obtain a halogenated benzenerepresented by formula (III), and

a step of subsequently nitrating the halogenated benzene to obtain ahalogenated nitrobenzene represented by formula (II).

[6] The method for producing a halogenated nitrobenzene disclosed abovein [5], wherein fuming sulfuric acid and concentrated nitric acid areadded to the halogenated benzene represented by formula (III) to nitratethe halogenated benzene.

[7] The method for producing a halogenated nitrobenzene disclosed abovein [5], wherein fuming sulfuric acid and fuming nitric acid are added tothe halogenated benzene represented by formula (III) to nitrate thehalogenated benzene.

[8] A method for producing a halogenated aniline, including a step ofreducing a halogenated nitrobenzene represented by formula (II) toobtain a halogenated aniline represented by formula (I).

[9] A method for producing 2,3-difluoroaniline, including a step ofdehalogenating a halogenated aniline represented by formula (I).

[10] A method for producing 2,3-difluoroaniline, including:

a step of reducing a halogenated nitrobenzene represented by formula(II) to obtain a halogenated aniline represented by formula (I), and

a step of dehalogenating the halogenated aniline.

[11] A method for producing 1,2-dichloro-4,5-difluorobenzene, includinga step of chlorinating 1,2-difluorobenzene.

Effects of the Invention

The halogenated aniline according to the present invention can be usedto easily produce 2,3-difluoroaniline, which is a production rawmaterial for2-[2-fluoro-6-(7,8-difluoro-2-methylquinolin-3-yloxy)phenyl]propan-2-olor 2-[2-fluoro-6-(7,8-difluoroquinolin-3-yloxy)phenyl]propan-2-ol or thelike. Further, by using the production method of the present invention,the halogenated aniline can be produced cheaply, easily, and in largequantities.

BEST MODE FOR CARRYING OUT THE INVENTION

The halogenated aniline according to the present invention is a compoundrepresented by formula (I). In formula (I), each of X¹ and X²independently represents a chlorine atom, a bromine atom or an iodineatom.

Specific examples of the halogenated aniline according to the presentinvention include 2,3-dichloro-5,6-difluoroaniline,2,3-dibromo-5,6-difluoroaniline, 3-bromo-2-chloro-5,6-difluoroaniline,2-bromo-3-chloro-5,6-difluoroaniline,2-chloro-3-iodo-5,6-difluoroaniline, and2-iodo-3-chloro-5,6-difluoroaniline.

The halogenated nitrobenzene according to the present invention is acompound represented by formula (IIa). In formula (IIa), each of X^(1a)and X^(2a) independently represents a chlorine atom, a bromine atom oran iodine atom. However, the case in which X^(1a) and X^(2a) bothrepresent bromine atoms is excluded.

Specific examples of the halogenated nitrobenzene according to thepresent invention include 1,2-dichloro-4,5-difluoro-3-nitrobenzene,1-bromo-2-chloro-4,5-difluoro-3-nitrobenzene,2-bromo-1-chloro-4,5-difluoro-3-nitrobenzene,1-iodo-2-chloro-4,5-difluoro-3-nitrobenzene, and1-chloro-2-iodo-4,5-difluoro-3-nitrobenzene.

The halogenated aniline represented by formula (I) according to thepresent invention can be produced using 1,2-difluorobenzene or a1-halogeno-3,4-difluorobenzene as the starting raw material, byperforming the three steps described below.

The first step is a step of halogenating 1,2-difluorobenzene or a1-halogeno-3,4-difluorobenzene to produce a halogenated benzenerepresented by formula (III). In formula (III), each of X¹ and X²independently represents a chlorine atom, a bromine atom or an iodineatom.

The halogenation of the first step can be conducted under the type ofhalogenation conditions widely used in typical organic chemicalsynthesis reactions. Examples of halogenating agents that can be usedinclude molecular chlorine, molecular bromine, molecular iodine,sulfuryl chloride, sulfuryl bromide, N-chlorosuccinimide,N-bromosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin, and1,3-diiodo-5,5-dimethylhydantoin. Among these compounds, the use ofmolecular chlorine or molecular bromine is preferable.

The halogenation of 1,2-difluorobenzene preferably employs a catalyst.The catalyst is preferably a Lewis acid catalyst such as Fe, FeCl₃,FeBr₃, Fe₂O, Al, Al₂O₃, AlCl₃, a zeolite, ZrO₂, SbCl₃, SbCls, TiCl₄,SnCl₄ or MoCl₅. Among these, Fe, FeCl₃ or FeBr₃ is more preferable, andFe is particularly desirable.

The amount used of the catalyst, relative to the mass of the1,2-difluorobenzene raw material, is preferably from 0.1 to 50% by mass,and more preferably from 0.5 to 10% by mass. Alternatively, any ofvarious sulfur compounds may be added as co-catalysts for the purpose ofaltering the reaction selectivity or the reaction rate.

The reaction temperature may be set within a range from −40 to 200° C.,but if smooth progression of the reaction and the boiling point of theraw material are taken into consideration, then the reaction temperatureis preferably from 0 to 70° C., and more preferably from 40 to 60° C.The reaction is usually performed in the absence of a solvent, but asolvent that is inert during the halogenation, such as carbontetrachloride, chloroform, carbon disulfide or acetic acid, may be usedif necessary.

The second step is a step of nitrating the halogenated benzenerepresented by formula (III) to produce a halogenated nitrobenzenerepresented by formula (II). In formula (II), each of X¹ and X²independently represents a chlorine atom, a bromine atom or an iodineatom.

The nitration of the second step may employ typical nitration methodswidely used in organic chemical synthesis reactions. Examples of methodsthat may be used include nitration in a mixed acid system using at leastone of concentrated nitric acid, a nitrate salt and fuming nitric acid,and at least one of concentrated sulfuric acid and fuming sulfuric acid,nitration in glacial acetic acid or acetic anhydride solvent, andnitration in a fuming nitric acid system.

The above-mentioned nitration in a mixed acid system is preferably:

a method in which the nitration is performed by adding fuming sulfuricacid and fuming nitric acid to the halogenated benzene represented byformula (III),

a method in which the nitration is performed by adding fuming sulfuricacid and a nitrate salt to the halogenated benzene represented byformula (III),

a method in which the nitration is performed by adding concentratedsulfuric acid and fuming nitric acid to the halogenated benzenerepresented by formula (III), or

a method in which the nitration is performed by adding fuming sulfuricacid and concentrated nitric acid to the halogenated benzene representedby formula (III).

Among the above, a method in which the nitration is performed by addingfuming sulfuric acid and fuming nitric acid to the halogenated benzenerepresented by formula (III), and a method in which the nitration isperformed by adding fuming sulfuric acid and concentrated nitric acid tothe halogenated benzene represented by formula (III) are particularlypreferred.

The concentration of the concentrated nitric acid is preferably at least65%, and the concentration of the concentrated sulfuric acid ispreferably at least 90%.

The nitrate salt is preferably lithium nitrate, sodium nitrate,potassium nitrate, cesium nitrate, calcium nitrate or ammonium nitrate,and is more preferably sodium nitrate or potassium nitrate.

The reaction temperature is preferably at least −20° C. but not morethan 150° C., more preferably greater than 0° C. but not more than 90°C., and still more preferably at least 20° C. but not more than 70° C.

Alternatively, a solvent that is inert to the nitration, such asmethylene chloride or n-hexane, may be used if necessary.

The third step is a step of reducing the halogenated nitrobenzenerepresented by formula (II) to produce a halogenated aniline representedby formula (I).

The third step is performed by a hydrogenation using a reductioncatalyst. Examples of the reduction catalyst include Pd, Pt, Ni and Rh.Among these, Pd is preferred.

The amount used of the catalyst, calculated as a mass of the metalrelative to the mass of the 2,3-difluoro-5,6-dihalogenonitrobenzene, ispreferably from 0.01 to 2.5% by mass, and more preferably from 0.1 to 1%by mass.

The reaction temperature is preferably from 0 to 150° C., morepreferably from 10 to 100° C., and still more preferably from 40 to 70°C. The reaction pressure may be either normal pressure or an appliedpressure, and is preferably within a range from 0 to 50 kg/cm².

The reaction solvent is preferably a solvent that is inert to thehydrogenation reaction, and examples include lower alcohols such asmethyl alcohol and ethyl alcohol, ethers such as tetrahydrofuran anddioxane, hydrocarbons such as hexane and toluene, esters such as ethylacetate, water, and mixtures of these solvents. An acid such as aceticacid or hydrochloric acid may be added to the solvent. Further, a methodusing a typical Bechamp reduction may also be used.

By using the method for producing a halogenated aniline according to thepresent invention, a halogenated aniline represented by formula (I) canbe produced cheaply, easily and in large quantities, using1,2-difluorobenzene or a 1-halogeno-3,4-difluorobenzene as the startingraw material.

Further, the thus obtained halogenated aniline represented by formula(I) may or may not be isolated before supply to the dehalogenationreaction described below.

By subjecting the obtained halogenated aniline represented by formula(I) to a dehalogenation reaction, 2,3-difluoroaniline can be produced inhigh yield.

This dehalogenation reaction is performed by using a reduction catalystto effect a hydrogenation. A base such as triethylamine or caustic sodamay also be added during this reaction.

The 2,3-difluoroaniline can be used as a production raw material for2-[2-fluoro-6-(7,8-difluoro-2-methylquinolin-3-yloxy)phenyl]propan-2-oland 2-[2-fluoro-6-(7,8-difluoroquinolin-3-yloxy)phenyl]propan-2-ol,which are known agricultural and horticultural germicides.

EXAMPLES

The present invention is described below in further detail using aseries of examples. However, the present invention is in no way limitedby these examples. Compounds of the present invention obtained in thefollowing examples were isolated and purified, and the structuralformulas of the compounds were then identified by elemental analysis,NMR data analysis and melting point measurement, thereby confirming thecompounds as novel compounds.

Example 1 (Production of 1,2-dichloro-4,5-difluorobenzene)

First, 60.3 g (528.4 mmol) of 1,2-difluorobenzene and 1.0 g of anhydrousferric chloride were mixed, and with the mixture undergoing constantstirring, 178.3 g (2.51 mol) of chlorine gas was introduced into themixture over a period of 9 hours. During this period, the reactiontemperature was maintained between 48 and 54° C. The reaction system wasthen deaerated by flushing with nitrogen. Subsequently, 40 mL ofdichloromethane and 50 mL of water were added to the reaction mixture,and a phase separation was performed. The water layer was extracted withdichloromethane. The organic layers were combined and washed with asaturated aqueous solution of sodium sulfite. Quantitative analysis ofthe organic layer by HPLC revealed that the yield of1,2-dichloro-4,5-difluorobenzene was 63.3% (61.20 g, 334.5 mmol).

Example 2 (Production of 1,2-dibromo-4,5-difluorobenzene)

First, 11.41 g (100 mmol) of 1,2-difluorobenzene, 31.47 g (110 mmol) of1,3-dibromo-5,5-dimethylhydantoin and 62.30 g of acetic acid were mixed,and the mixture was cooled to 10° C. Subsequently, 49.15 g ofconcentrated sulfuric acid was added to the mixture, and a reaction wasperformed at 50° C. for 2.3 hours. An additional 1.46 g (5.1 mmol) of1,3-dibromo-5,5-dimethylhydantoin was then added, and the reaction wascontinued for 50 minutes. Subsequently, the reaction mixture wasextracted into 100 mL of hexane. The target compound was extracted fromthe waste acid layer using two 100 mL samples of hexane. The organiclayers were combined and washed twice with 50 mL samples of water, oncewith 50 mL of a saturated aqueous solution of sodium thiosulfate, twicewith 20 mL samples of a 1 mol/L aqueous solution of sodium hydroxide,and then once with 50 mL of water. Subsequently, the organic layer wasconcentrated under reduced pressure, yielding1,2-dibromo-4,5-difluorobenzene as a yellow oily substance in a yield of74% (73.80 mmol).

Example 3 (Production of 1,2-dibromo-4,5-difluorobenzene)

First, 84 mg (1.5 mmol) of iron powder was dispersed in 7.53 g (50 mmol)of 1,2-difluorobenzene, and the internal temperature was adjusted to 20°C. Subsequently, 18.4 g (115 mmol) of bromine was added dropwise over aperiod of 50 minutes. During this period, the internal temperature wasmaintained at about 20° C. Following the completion of the dropwiseaddition of bromine, the internal temperature was raised to 40° C., themixture was reacted for 2 hours, and the internal temperature was thenfurther raised to 50° C. and the reaction was continued for a further 2hours. Following completion of the reaction, the reaction mixture wascooled to room temperature and poured into an aqueous solution preparedby dissolving 25.2 g of sodium bicarbonate and 12.6 g of sodium sulfitein 100 ml of water. The product was then extracted with ethyl acetate.The extracted solution was washed once with each of water and asaturated saline solution, and was then dried over magnesium sulfate.Following removal of the magnesium sulfate by filtration, quantitativeanalysis of the solution by HPLC revealed a reaction yield of 94% of thetarget product 1,2-dibromo-4,5-difluorobenzene.

Example 4 (Production of 1-bromo-2-chloro-4,5-difluorobenzene)

First, 14.86 g (100 mmol) of 4-chloro-1,2-difluorobenzene, 15.73 g (55mmol) of 1,3-dibromo-5,5-dimethylhydantoin and 70 mL of acetic acid weremixed, and the mixture was cooled to 12° C. Subsequently, 30 mL ofconcentrated sulfuric acid was added to the mixture, and a reaction wasperformed at 50° C. for 1.7 hours. An additional 1.46 g (5.1 mmol) of1,3-dibromo-5,5-dimethylhydantoin was then added, and the reaction wascontinued for 2 hours. Subsequently, the reaction mixture was extractedinto 100 mL of hexane. The target compound was extracted from the wasteacid layer using two 100 mL samples of hexane and then a further 30 mLof hexane. The organic layers were combined and washed twice with 50 mLsamples of water, once with 50 mL of a saturated aqueous solution ofsodium thiosulfate, twice with 20 mL samples of a 1 mol/L aqueoussolution of sodium hydroxide, once with 30 mL of water, and then oncewith a saturated saline solution. Subsequently, the organic layer wasconcentrated under reduced pressure, yielding 17.36 g (yield: 76%) of1-bromo-2-chloro-4,5-difluorobenzene as yellow crystals.

Example 5 (Production of 1,2-dichloro-4,5-difluoro-3-nitrobenzene)

First, 7.74 g (42.32 mmol) of 1,2-dichloro-4,5-difluorobenzene and 17.54g of 30% by mass fuming sulfuric acid were mixed, and the mixture washeated to 20° C. Subsequently, 4.87 g (75.0 mmol) of 97% by mass fumingnitric acid was added dropwise to the mixture over a period of 2 hourswith the temperature maintained at 20 to 26° C. Following completion ofthe dropwise addition, the resulting mixture was stirred at 20 to 26° C.for 2 hours. An additional 0.20 g (3.1 mmol) of 97% by mass fumingnitric acid was then added, and the resulting mixture was stirred for afurther 3 hours. The reaction mixture was then poured into ice water andextracted into 50 mL of dichloromethane, and the water layer was thentwice extracted with 20 mL samples of dichloromethane. The organiclayers were combined, washed with water, and then concentrated underreduced pressure, yielding 1,2-dichloro-4,5-difluoro-3-nitrobenzene in ayield of 71%.

1,2-dichloro-4,5-difluoro-3-nitrobenzene

¹H-NMR (400 MHz, CDCl₃): δ 7.56 (dd, 1H)

Example 6 (Production of 1,2-dichloro-4,5-difluoro-3-nitrobenzene)(using potassium nitrate)

First, 1.83 g (10 mmol) of 1,2-dichloro-4,5-difluorobenzene wassuspended in 5.6 mL of 30% by mass fuming sulfuric acid, and 2.02 g (20mmol) of potassium nitrate was added gradually in small amounts to thesuspension. A significant amount of heat was generated during thisaddition, and so the operation was performed under cooling in a waterbath so that the internal temperature did not exceed 26° C. Followingcompletion of the addition of the potassium nitrate, the reactionmixture was stirred for 2 hours. During this period, the internaltemperature increased naturally to 35° C. Subsequently, the reactionmixture was poured onto ice, and the product was extracted with ethylacetate. The resulting ethyl acetate solution was washed with water, andthen with a saturated aqueous solution of sodium bicarbonate and asaturated saline solution, before being dried over magnesium sulfate.Quantitative analysis of the solution by HPLC revealed a yield of 31% ofthe target product 1,2-dichloro-4,5-difluoro-3-nitrobenzene.

Example 7 (Production of 1,2-dibromo-4,5-difluoro-3-nitrobenzene)

First, 6.80 g (25.0 mmol) of 1,2-dibromo-4,5-difluorobenzene and 18.54 gof 100% by mass sulfuric acid were mixed, and the resulting mixture wasthen heated to 50° C. A mixed acid prepared from 2.5 g (38.5 mmol) of97% by mass fuming nitric acid and 9.30 g of 100% by mass sulfuric acidwas then added dropwise to the mixture and reacted over a period of 130minutes. The reaction temperature was maintained at 50 to 52° C. Theresulting mixture was then poured into ice water, and 82.3 g of a 28% bymass aqueous solution of sodium hydroxide was added to neutralize themixture. The precipitated crystals were collected by filtration. Thefiltrate was extracted with 200 mL of dichloromethane, the filteredcrystals were also dissolved in this dichloromethane, and the resultingsolution was concentrated under reduced pressure. The 6.21 g of the thusobtained crude crystals (crude yield: 78%) was recrystallized from amixed solution of methanol and water, yielding 4.60 g (14.52 mmol,yield: 58%) of a yellowy white powder of1,2-dibromo-4,5-difluoro-3-nitrobenzene.

1,2-dibromo-4,5-difluoro-3-nitrobenzene

¹H-NMR (400 MHz, CDCl₃): δ 7.70 (dd, 1H)

Example 8 (Production of 1,2-dibromo-4,5-difluoro-3-nitrobenzene) (usingpotassium nitrate)

First, 2.71 g (10 mmol) of 1,2-dibromo-4,5-difluorobenzene was suspendedin 5.6 mL of 30% by mass fuming sulfuric acid, and 2.02 g (20 mmol) ofpotassium nitrate was added gradually in small amounts to thesuspension. A significant amount of heat was generated during thisaddition, and so the operation was performed under cooling in a waterbath so that the internal temperature did not exceed 20° C. Followingcompletion of the addition of the potassium nitrate, the internaltemperature was raised to 35° C., and the reaction mixture was stirredfor 2 hours 30 minutes, before being cooled to room temperature.Subsequently, the reaction mixture was poured onto ice, and the productwas extracted with ethyl acetate. The resulting ethyl acetate solutionwas washed twice with water, and then with a saturated aqueous solutionof sodium bicarbonate and a saturated saline solution, before beingdried over magnesium sulfate. Quantitative analysis of the solution byHPLC revealed a yield of 41% of the target product1,2-dibromo-4,5-difluoro-3-nitrobenzene.

Example 9 (Production of 1,2-dibromo-4,5-difluoro-3-nitrobenzene) (using90% nitric acid)

First, 5.6 mL of 30% by mass fuming sulfuric acid was cooled to 5° C.,and 1.05 g of 90% nitric acid (equivalent to 15 mmol of nitric acid) wasthen added gradually. Following completion of the addition, thetemperature was raised to room temperature, and after stirring for 5minutes, 2.71 g (10 mmol) of 1,2-dibromo-4,5-difluorobenzene was added.The temperature of the reaction mixture was raised to 35° C., themixture was stirred for 1 hour 30 minutes, the temperature was thenfurther raised to 45° C., and the mixture was stirred for a further 30minutes, before being cooled to room temperature. The reaction mixturewas poured onto ice, and the product was extracted with ethyl acetate.The resulting ethyl acetate solution was washed twice with water, andthen with a saturated aqueous solution of sodium bicarbonate and asaturated saline solution, before being dried over magnesium sulfate andthen concentrated. The thus obtained crude crystals were purified bysilica gel column chromatography, yielding 2.91 g (9.18 mmol, yield:92%) of the target product 1,2-dibromo-4,5-difluoro-3-nitrobenzene.

Example 10 (Production of 1,2-dibromo-4,5-difluoro-3-nitrobenzene)

First, 8 mL of 30% by mass fuming sulfuric acid was cooled to 5° C., and1.45 g of 65% nitric acid (equivalent to 15 mmol of nitric acid) wasthen added gradually. Following completion of the addition, thetemperature was raised to room temperature, and after stirring for 5minutes, 2.71 g (10 mmol) of 1,2-dibromo-4,5-difluorobenzene was added.The temperature of the reaction mixture was raised to 35° C., themixture was stirred for 1 hour 30 minutes, and the temperature was thencooled to room temperature. The reaction mixture was poured onto ice,and the product was extracted with ethyl acetate. The resulting ethylacetate solution was washed twice with water, and then with a saturatedaqueous solution of sodium bicarbonate and a saturated saline solution,before being dried over magnesium sulfate. The magnesium sulfate wasthen removed by filtration, and quantitative analysis of the resultingsolution by HPLC revealed a reaction yield of 94% of the target product1,2-dibromo-4,5-difluoro-3-nitrobenzene.

Example 11 (Production of 2,3-dichloro-5,6-difluoroaniline)

First, 1.141 g (5.0 mmol) of 1,2-dichloro-4,5-difluoro-3-nitrobenzenewas dissolved in a mixed solution of 5 mL of ethanol and 2.5 mL ofwater, and 0.8458 g (15.15 mmol) of iron powder and 0.5557 g (5.01 mmol)of calcium chloride were then added to the solution. The resultingmixture was heated to 60° C. and stirred for 1.3 hours. The mixture wasthen filtered, and the resulting filtrate was concentrated under reducedpressure, yielding 1.11 g of a brown-colored amorphous crude product.The crude product was purified by silica gel column chromatography,yielding 0.85 g (yield: 86%) of 2,3-dichloro-5,6-difluoroaniline as anorange-colored oily substance.

2,3-dichloro-5,6-difluoroaniline

¹H-NMR (400 MHz, CDCl₃): δ 6.70 (dd, 1H), 4.36 (brs, 2H)

Example 12 (Production of 2,3-dibromo-5,6-difluoroaniline)

First, 1.57 g (4.95 mmol) of 1,2-dibromo-4,5-difluoro-3-nitrobenzene wasdissolved in a mixed solution of 5 mL of ethanol and 2.5 mL of water,and 0.85 g (15.2 mmol) of iron powder and 0.54 g (4.87 mmol) of calciumchloride were then added to the solution. The resulting mixture washeated to 55° C. and stirred for 3.2 hours. The mixture was thenfiltered, and the resulting filtrate was concentrated under reducedpressure. The concentrate was purified by silica gel columnchromatography, yielding 1.25 g (yield: 88%) of skin-colored crystals of2,3-dibromo-5,6-difluoroaniline.

2,3-dibromo-5,6-difluoroaniline

¹H-NMR (400 MHz, CDCl₃): δ 6.91 (dd, 1H), 4.45 (brs, 2H)

Example 13 (Production of mixture of3-bromo-2-chloro-5,6-difluoroaniline and2-bromo-3-chloro-5,6-difluoroaniline)

First, 0.818 g (3.00 mmol) of a mixture of1-bromo-2-chloro-4,5-difluoro-3-nitrobenzene and2-bromo-1-chloro-4,5-difluoro-3-nitrobenzene (molar ratio 6:4) wasdissolved in a mixed solution of 3 mL of ethanol and 1.5 mL of water,and 0.517 g (9.26 mmol) of iron powder and 0.335 g (3.02 mmol) ofcalcium chloride were then added to the solution. The resulting mixturewas heated to 60° C. and stirred for 1.7 hours. The mixture was thenfiltered, the resulting filtrate was concentrated under reducedpressure, and the thus obtained crude product was purified by silica gelcolumn chromatography, yielding 0.56 g (yield: 77%) of skin-coloredcrystals of a mixture of 3-bromo-2-chloro-5,6-difluoroaniline and2-bromo-3-chloro-5,6-difluoroaniline (molar ratio 6:4).

3-bromo-2-chloro-5,6-difluoroaniline

¹H-NMR (400 MHz, CDCl₃): δ 6.73 (dd, 1H)

2-bromo-3-chloro-5,6-difluoroaniline

¹H-NMR (400 MHz, CDCl₃): δ 6.85 (dd, 1H)

Example 14 (Production of 2,3-difluoroaniline)

First, 0.506 g (1.76 mmol) of 2,3-dibromo-5,6-difluoroaniline wasdissolved in 3.5 mL of methanol, and then 35.6 mg of 10% Pd/C (50% wet)and 0.722 g (7.05 mmol) of triethylamine were added. The atmosphereinside the reaction vessel was substituted with hydrogen, and thereaction mixture was reacted at 50° C. for 3 hours under slight hydrogenpressurization. Subsequently, the catalyst was removed by filtration.The resulting liquid was subjected to quantitative analysis by HPLC. Theyield of 2,3-difluoroaniline was 98%.

Example 15 (Production of 2,3-difluoroaniline)

First, 1.147 g (5.03 mmol) of 1,2-dichloro-4,5-difluoro-3-nitrobenzenewas dissolved in 10 mL of methanol, and then 100 mg of 10% Pd/C (50%wet) and 2.02 g (20.0 mmol) of triethylamine were added. The atmosphereinside the reaction vessel was substituted with hydrogen, and thereaction mixture was reacted at 45° C. for 2.8 hours under slighthydrogen pressurization. Analysis of the resulting reaction product byHPLC revealed 17.4 area % of 2,3-dichloro-5,6-difluoroaniline as aresidual intermediate. Reaction was continued under the same conditionsfor a further 1.4 hours. The catalyst was then removed by filtration.The resulting liquid was subjected to quantitative analysis by HPLC. Theyield of 2,3-difluoroaniline was 62%. The intermediate2,3-dichloro-5,6-difluoroaniline existed in a residual amount of 6.4area %.

Example 16 (Production of 2,3-difluoroaniline)

First, 0.638 g (2.01 mmol) of 1,2-dibromo-4,5-difluoro-3-nitrobenzenewas dissolved in 4 mL of methanol, and then 48.4 mg of 10% Pd/C (50%wet) and 6.2 mg (0.06 mmol) of triethylamine were added. The atmosphereinside the reaction vessel was substituted with hydrogen, and thereaction mixture was reacted at 50° C. for 2 hours under slight hydrogenpressurization. Analysis of the resulting reaction product by HPLCrevealed 2.2 area % of 2,3-dibromo-5,6-difluoroaniline as a residualintermediate. Reaction was continued under the same conditions for afurther 0.5 hours. The catalyst was then removed by filtration. Theresulting liquid was subjected to quantitative analysis by HPLC. Theyield of 2,3-difluoroaniline was 93%. The intermediate2,3-dibromo-5,6-difluoroaniline had been eliminated.

Example 17 (Production of 2,3-difluoroaniline)

First, 1.583 g (5.00 mmol) of 1,2-dibromo-4,5-difluoro-3-nitrobenzenewas dissolved in 10 mL of methanol, and then 100 mg of 10% Pd/C (50%wet) and 2.03 g (20.1 mmol) of triethylamine were added. The atmosphereinside the reaction vessel was substituted with hydrogen, and thereaction mixture was reacted at 40° C. for 7 hours under slight hydrogenpressurization. Subsequently, the catalyst was removed by filtration.The resulting liquid was subjected to quantitative analysis by HPLC. Theyield of the target product 2,3-difluoroaniline was 86%. Theintermediate 2,3-dibromo-5,6-difluoroaniline had been eliminated.

Example 18 (Production of 2,3-difluoroaniline)

First, 0.953 g (4.19 mmol) of 1,2-dichloro-4,5-difluoro-3-nitrobenzenewas dissolved in 10 mL of methanol, and then 115.7 mg of 10% Pd/C(47.40% wet) and 2.02 g (20.0 mmol) of triethylamine were added. Theatmosphere inside the reaction vessel was substituted with hydrogen, andthe reaction mixture was reacted at 40° C. for 2.0 hours under slighthydrogen pressurization. Subsequent analysis of the reaction mixture byHPLC revealed that the raw material1,2-dichloro-4,5-difluoro-3-nitrobenzene had been eliminated. Reactionwas continued under the same conditions for a further 0.7 hours. Thecatalyst was then removed by filtration. The resulting liquid wassubjected to quantitative analysis by HPLC. The yield of2,3-difluoroaniline was 52.4%. The intermediate2,3-dichloro-5,6-difluoroaniline existed in a residual amount of 7.27area %.

INDUSTRIAL APPLICABILITY

The halogenated aniline and the halogenated nitrobenzene according tothe present invention are useful as production intermediates for2,3-difluoroaniline. Moreover, 2,3-difluoroaniline is useful as aproduction intermediate for the active ingredients for agricultural andhorticultural germicides such as2-[2-fluoro-6-(7,8-difluoro-2-methylquinolin-3-yloxy)phenyl]propan-2-oland 2-[2-fluoro-6-(7,8-difluoroquinolin-3-yloxy)phenyl]propan-2-ol.

The invention claimed is:
 1. A method for producing a halogenatednitrobenzene, comprising: a step of halogenating 1,2-difluorobenzene ora 1-halogeno-3,4-difluorobenzene to obtain a halogenated benzenerepresented by formula (III):

 wherein each of X¹ and X² independently represents a chlorine atom, abromine atom or an iodine atom, and a step of subsequently nitrating thehalogenated benzene to obtain a halogenated nitrobenzene represented byformula (II):

 wherein each of X¹ and X² independently represents a chlorine atom, abromine atom or an iodine atom.
 2. The method for producing ahalogenated nitrobenzene according to claim 1, wherein fuming sulfuricacid and concentrated nitric acid are added to the halogenated benzenerepresented by formula (III) to nitrate the halogenated benzene.
 3. Themethod for producing a halogenated nitrobenzene according to claim 1,wherein fuming sulfuric acid and fuming nitric acid are added to thehalogenated benzene represented by formula (III) to nitrate thehalogenated benzene.